Bim-mediated attrition of virus-specific CD8 T cells in chronic HBV infection
Lead Research Organisation:
University College London
Department Name: Immunology and Molecular Pathology
Abstract
Hepatitis B virus remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease, leading to liver failure and liver cancer. There is a vaccine to prevent spread, but this is of no use to the 400 million people estimated to already be chronically infected. There are now a number of drugs available to treat hepatitis B infection but these typically only suppress the virus rather than clear it; when the patient stops the treatment the virus level comes back up.
The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.
The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.
Technical Summary
Persistent infection with hepatitis B virus (HBV) continues to account for more than a million deaths a year worldwide from liver cirrhosis and hepatocellular carcinoma. Existing therapies usually suppress rather than cure infection, necessitating long-term maintenance use of drugs with ongoing limitations of cost, viral resistance and toxicity. There is therefore a pressing need to complement antiviral therapy with a targeted immunotherapeutic approach aiming to restore effective immune control of HBV and achieve sustained off-treatment responses.
CD8 T cells are known to be critical to the control of HBV and are markedly depleted in patients with persistent infection. We have identified a dysregulated apoptotic pathway in these cells that contributes to their attrition. The pro-apoptotic protein Bim (Bcl-2-interacting mediator) was found to be upregulated in HBV-specific CD8 T cells in patients with chronic compared to resolved HBV infection; downstream inhibition of this pathway rescued HBV-specific CD8 directly ex vivo (Lopes et al JCI May 2008). We hypothesise that blocking Bim-mediated apoptosis will allow successful reconstitution of HBV-specific CD8 T cells able to control infection.
The underlying mechanism responsible for the induction of Bim in HBV-specific CD8 may be related to excessive TCR triggering, to presentation of antigen by infected hepatocytes, or to cross-presentation of HBV antigens. We will investigate in vitro the contribution of each of these processes to triggering this pro-apoptotic pathway in HBV-specific CD8. We will also address the role of aberrant 41BB signalling and any potential to counteract Bim-mediated apoptosis by correcting this. We will use this experimental set-up to explore the potential to block the induction of Bim using immunosuppressive or non-immunosuppressive cyclophilin inhibitors.
To determine the contribution of Bim-mediated apoptosis to loss of the HBV-specific response in vivo, we will use transgenic mice that replicate HBV at high levels in the liver. When HBV-specific CD8 are infused into these mice they are known to undergo premature death; we will investigate whether this is mediated through the Bim pathway using Bim knockout mice.
Finally we will examine whether current treatment regimes for chronic HBV infection have any impact on Bim-mediated apoptosis of HBV-specific CD8.
By identifying underlying triggers and testing the potential of blocking approaches in vitro and in vivo, this work will inform future targeted therapeutic interventions to re-programme the pro-apoptotic defect of HBV-specific CD8 T cells.
CD8 T cells are known to be critical to the control of HBV and are markedly depleted in patients with persistent infection. We have identified a dysregulated apoptotic pathway in these cells that contributes to their attrition. The pro-apoptotic protein Bim (Bcl-2-interacting mediator) was found to be upregulated in HBV-specific CD8 T cells in patients with chronic compared to resolved HBV infection; downstream inhibition of this pathway rescued HBV-specific CD8 directly ex vivo (Lopes et al JCI May 2008). We hypothesise that blocking Bim-mediated apoptosis will allow successful reconstitution of HBV-specific CD8 T cells able to control infection.
The underlying mechanism responsible for the induction of Bim in HBV-specific CD8 may be related to excessive TCR triggering, to presentation of antigen by infected hepatocytes, or to cross-presentation of HBV antigens. We will investigate in vitro the contribution of each of these processes to triggering this pro-apoptotic pathway in HBV-specific CD8. We will also address the role of aberrant 41BB signalling and any potential to counteract Bim-mediated apoptosis by correcting this. We will use this experimental set-up to explore the potential to block the induction of Bim using immunosuppressive or non-immunosuppressive cyclophilin inhibitors.
To determine the contribution of Bim-mediated apoptosis to loss of the HBV-specific response in vivo, we will use transgenic mice that replicate HBV at high levels in the liver. When HBV-specific CD8 are infused into these mice they are known to undergo premature death; we will investigate whether this is mediated through the Bim pathway using Bim knockout mice.
Finally we will examine whether current treatment regimes for chronic HBV infection have any impact on Bim-mediated apoptosis of HBV-specific CD8.
By identifying underlying triggers and testing the potential of blocking approaches in vitro and in vivo, this work will inform future targeted therapeutic interventions to re-programme the pro-apoptotic defect of HBV-specific CD8 T cells.
Organisations
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ORCID iD |
| Mala Maini (Principal Investigator) |